Randomized trial of allogeneic related bone marrow transplantation versus peripheral blood stem cell transplantation for chronic myeloid leukemia

Article Outline

• Abstract
• Introduction
• Patients and methods
  • Study design
  • Treatment and supportive care
  • Monitoring for persistent or recurrent CML
  • Management of chronic GVHD
  • Quality of life
  • Statistical analysis
• Results
  • Patient outcomes
  • Monitoring and interventions for persistent or recurrent CML
  • Graft-versus-host disease
  • Quality of life
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

Seventy-two chronic myeloid leukemia patients were enrolled as part of a larger randomized trial at 3 centers between March 1996 and July 2001 to undergo either HLA-matched related allogeneic bone marrow (BM) or filgrastim (granulocyte colony-stimulating factor)-mobilized peripheral blood stem cell (PBSC) transplantation. Forty patients received BM, and 32 patients received PBSCs. There was no statistically significant difference in the incidence of acute or chronic graft-versus-host disease (GVHD), overall survival, disease-free survival, or non-relapse-related mortality between patients receiving BM or PBSC transplants. The cumulative incidence of grade II to IV acute GVHD was 49% in BM and 55% in PBSC recipients (P = .48). The cumulative incidence of clinical extensive chronic GVHD was 50% in BM and 59% in PBSC recipients (P = .46). Among 62 chronic phase chronic myeloid leukemia patients, there was no significant difference in overall survival (87% versus 81%; P = .59), disease-free survival (80% versus 81%; P = .61), or non-relapse-related mortality (13% versus 19%; P = .60) by cell source (BM versus PBSCs). Among chronic phase patients, however, there was a trend toward a higher cumulative incidence of relapse at 3 years in BM recipients (7% versus 0%; P = .10) and a higher cumulative incidence of chronic GVHD in PBSC recipients (59% versus 40%; P = .11). The trend toward a higher relapse incidence in BM recipients persisted with a longer follow-up.

Key words:  Chronic myeloid leukemia , Related allogeneic bone marrow transplantation , Peripheral blood stem cell transplantation , Randomized trial

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Introduction 

Peripheral blood stem cells (PBSCs) are increasingly selected as a source of hematopoietic stem cells for transplantation. The potential benefits of PBSCs include ease of collection, fewer adverse events reported in donors receiving granulocyte colony-stimulating factor [1], and more rapid hematologic and immune reconstitution [2, 3]. A major concern has been whether the absolute increase in T-cell dose in PBSC products results in increased acute or chronic graft-versus-host disease (GVHD). However, an increased T-cell dose may translate into fewer relapses via enhanced graft-versus-leukemia (GVL) effects. Most retrospective and subsequent randomized studies have reported no increase in the incidence of acute GVHD among patients receiving PBSC and have reported equivocal results with regard to the incidence of chronic GVHD [3, 4, 5, 6, 7, 8]. Only 1 study has found improved overall survival (OS) in PBSC recipients, as a consequence of lower non-relapse-associated mortality (NRM) [5]. Two studies have suggested that disease-free survival (DFS) was improved in patients receiving PBSCs for the treatment of advanced myeloid malignancies [4, 5]. We report an update of results from a prospectively defined cohort of chronic phase (CP) and accelerated phase (AP) chronic myeloid leukemia (CML) patients enrolled in a randomized trial at the Fred Hutchinson Cancer Research Center (FHCRC), City of Hope National Medical Center (COHNMC), and Stanford University Medical Center (SUMC) [4].

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Patients and methods 

Study design 

Seventy-two CML-CP and -AP patients were enrolled in an extended randomized trial at the FHCRC, the COHNMC, and SUMC. Accrual began in March 1996. The initial randomized trial compared bone marrow (BM) and PBSCs for several hematologic malignancies, including CML [4]. These CML patients and subsequent CML CP or AP patients were enrolled onto an extended randomized study comparing the 2 sources of stem cells to address engraftment, GVHD, and GVL effects specifically in patients with CML. Fifty-seven of the 72 patients were previously reported as part of the initial randomized trial [4]. The extended study was closed early in July 2001 because of slow accrual, which was due in part to publication of the initial randomized study that suggested the benefit of PBSC and in part to the increased use of imatinib mesylate. The study protocol was reviewed and approved by the institutional review boards of all participating centers. Fifty-four patients were treated at the FHCRC, 11 at the COHNMC, and 7 at SUMC. Enrollment criteria for patients and donors were as previously described [4].

Treatment and supportive care 

Sixty-eight patients received busulfan 4 mg/kg by mouth in divided doses daily for 4 days (total dose, 16 mg/kg) and cyclophosphamide 60 mg/kg once daily intravenously days 1 and 2 (total dose, 120 mg/kg). Busulfan was targeted at 900 ng/mL as previously described [9]. Four patients received total body irradiation (total dose, 1320 cGy) and etoposide (total dose, 60 mg/kg).

Standard techniques for marrow and PBSC collection [4] and GVHD prophylaxis with cyclosporin and methotrexate were as previously described [10, 11]. For GVHD analysis, the number and duration of GVHD therapies were calculated. For this analysis, the number of therapies reflected any change in treatment, such as reinstitution of immunosuppressive therapy, an increase in steroid dose, or initiation of a new therapy [12]. Antibiotics and infection prophylaxis were administered according to each center’s policies for prevention of bacterial, fungal, and viral infections.

Monitoring for persistent or recurrent CML 

Disease relapse was monitored by pathology, cytogenetics, and qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) on days 28 and 80, at 6-month intervals up to 2 years, and then yearly after 2 years. FHCRC patients were also monitored by quantitative PCR. The techniques of qualitative and quantitative RT-PCR for bcr-abl have been previously published [13, 14]. For analysis, relapse was defined as hematologic relapse, as cytogenetic relapse characterized by the presence of 5 or more Philadelphia chromosomes on a single cytogenetic analysis, or as the presence of any Philadelphia chromosome on at least 2 consecutive cytogenetic evaluations [4, 14].

Management of chronic GVHD 

Patients with chronic GVHD received treatment for at least 9 months unless a change in therapy was indicated. As previously documented [12], secondary chronic GVHD therapy was initiated for the progression of symptoms after at least 2 weeks of therapy, an absence of improvement after 1 month of therapy, persistent symptoms after 9 to 12 months of therapy after an initial improvement, or the recurrence of symptoms after cessation of immunosuppressive therapy.

Quality of life 

Karnofsky performance status (KPS) was measured at each institution for almost all patient visits. For patients who underwent transplantation at the FHCRC, an annual patient health questionnaire that addresses quality-of-life issues was instituted in 2000. The questionnaire addresses several areas: activity as related to overall health, current symptoms, medical complications, and other aspects of life as they relate to overall health. Specific questions address health behavior and general quality of life, including suicidal thoughts, memory difficulties, concerns about sexual function, worries about health status and insurance coverage, other medical problems, and ability to function at work, home, or school. Whenever possible, the fourth-year questionnaire was selected to compare outcomes between PBSC and BM recipients. If this questionnaire was not available, then the third- or fifth-year questionnaire was used.

Statistical analysis 

Estimates of OS and DFS were calculated by the Kaplan-Meier method [15]. The cumulative incidences of acute and chronic GVHD, relapse, and NRM were estimated by the methods described in Prentice and Kalbfleisch [16]. The statistical significance of differences in event rates was evaluated with the proportional hazards regression model. Death was treated as a competing risk in the analysis of acute and chronic GVHD and relapse. Relapse was treated as a competing risk in the analysis of chronic GVHD and NRM. All P values are based on likelihood ratio statistics and are 2 sided. Intention-to-treat analysis was used for all comparisons. The trial was designed to enroll 50 patients per study arm to have 80% power to detect a deleterious difference with respect to the rate of relapse, ie, a rate of 25% (based on a binomial difference) in PBSC recipients compared with an expected rate of 5% in BM recipients. However, because of a longer-than-anticipated accrual time, accrual was limited to 72 patients (40 BM and 32 PBSC recipients). The power to detect a deleterious difference with respect to relapse was 67%. For the subanalysis of CP patients only (30 BM and 32 PBSC recipients), the power was 59%.

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Results 

Patient outcomes 

The median patient age was 43 years (range, 18–61 years) and was not significantly different between the PBSC and BM recipients. The median time from diagnosis to transplantation was 6 months (range, 2-92 months). For CP patients, the time from diagnosis to transplantation was not significantly different between the BM and PBSC groups. The median time to transplantation was 6.0 months (range, 2.5–28.4 months) for BM recipients and 8.2 months (range, 3.0-51.9 months) for PBSC recipients. Sixty-two patients were in CP, and 10 patients were in AP. In the CP group, 30 patients received BM and 32 patients received PBSC transplants. All 10 AP patients were randomized to BM (P = .001).

Outcomes by cell source are reported in Table 1. All patients engrafted. The time intervals from transplantation to engraftment of both neutrophils and platelets were shorter in the PBSC group. The median time to neutrophil engraftment was 21.5 days in the BM group, compared with 16.5 days in the PBSC group (P = .03). The median time to platelet engraftment was 21.0 days in the BM group, compared with 14.0 days in the PBSC group (P = .26). Because of the unexpected randomization of all 10 AP patients to the BM arm, a subanalysis of CP patients was performed to assess the effect of cell source on the incidence of acute and chronic GVHD, NRM, relapse, DFS, and OS in this group.

Table 1. Outcomes of CML Patients Who Underwent Transplantation with BM or PBSCs, by Cell Source

Variable	BM	PBSCs	P Value
Engraftment
Neutrophil (d)	21.5	16.5	.03
Platelet (d)	21	14	.26
Acute GVHD
Grades ≥II	49%	55%	.48
Chronic GVHD
Clinical extensive
All patients	50%	59%	.46
Chronic phase only	40%	59%	.11
Nonrelapse mortality*
All patients	20%	19%	.86
Chronic phase only	13%	19%	.60
Relapse*
All patients	15%	0%	.01
Chronic phase only	7%	0%	.10
Survival†
All patients	72%	81%	.42
Chronic phase only	87%	81%	.59
Disease-free survival†
All patients	65%	81%	.10
Chronic phase only	80%	81%	.61

Among the 30 CML-CP BM recipients, there were 4 (13%) nonrelapse deaths, and among the 32 CML-CP PBSC recipients, there were 6 (19%) nonrelapse deaths. The major causes of NRM among all patients included diffuse alveolar damage/interstitial pneumonitis, infection, and acute GVHD. Four patients died before day 100: 1 BM recipient on day 37 and 3 PBSC recipients on days 46, 69, and 94. We found no statistically significant difference in NRM, DFS, OS, or the incidence of acute or chronic GVHD by cell source among CML patients in CP (Table 1 and Figure 1). As shown in Figure 2, we found a trend toward a decrease in relapse in CP PBSC recipients. As reported in Table 1, the cumulative incidence estimate of relapse at 3 years was 7% in CP BM recipients, compared with 0% in PBSC recipients (P = .10). As of last contact, there were 4 (13%) relapses in CP BM recipients, and there was 1 (3%) relapse in CP PBSC recipients. Two relapses occurred in the BM group on day 1111 and day 1469. One late relapse occurred in the PBSC group on day 1844 (Figure 2).

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• Figure 1. 

  Overall survival and disease-free survival by cell source in CML-CP patients.

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• Figure 2. 

  Relapse by cell source in CML-CP patients.

Monitoring and interventions for persistent or recurrent CML 

Four AP and 5 CP patients had recurrent CML. Outcomes and interventions in these 9 patients are summarized in Table 2. Three of 4 AP patients died from progressive disease. The fourth AP patient was successfully treated for cytogenetic relapse at 12 months with a rapid taper of immunosuppression, which was complicated only by a mild flare of hepatic GVHD. As of last contact 3 years after relapse, this patient has no molecular evidence of disease detectable by PCR. All 5 CP patients with recurrent CML have been successfully treated. Two patients achieved complete cytogenetic and molecular remissions, 1 during treatment with interferon (INF) and the other during treatment with imatinib mesylate. The third patient remains in cytogenetic remission during treatment with INF but has persistent low-level disease detectable by PCR. The fourth patient had minimal response during treatment with INF and cytarabine followed by donor lymphocyte infusion, but subsequent treatment with imatinib produced a complete molecular response. The fifth patient achieved a molecular remission 4 months after donor lymphocyte infusion after unsuccessful treatment with imatinib and imatinib and cytarabine during the previous 3 years. Follow-up for these patients ranges from 3 to 36 months after initiation of treatment for recurrent CML.

Table 2. Outcomes and Interventions in 9 Relapsed Patients

H indicates hematologic relapse; C, cytogenetic relapse; CCyR, complete cytogenetic response; CMR, complete molecular response; NED, no evident disease; Ara-C, cytarabine; DLI, donor lymphocyte infusion; INF, interferon.

Posttransplantation qualitative RT-PCR data for bcr-abl were available for analysis for 58 of 62 CML-CP patients enrolled in the randomized trial. Sixteen of 29 BM and 10 of 29 PBSC recipients had at least 1 positive qualitative PCR test. The probability of molecular relapse—defined as a single positive PCR test result—was 55% in BM recipients and 35% in PBSC recipients at 3 years (P = .10; Figure 3). There was a trend toward a higher probability of relapse among patients with a single positive qualitative PCR test. However, because of the small number of relapses, this association did not reach statistical significance. Quantitative RT-PCR data were available for analysis in 41 of 44 CML-CP patients who underwent transplantation at the FHCRC. The median number of tests performed was 6 (range, 1-17). There was a trend toward higher bcr-abl transcript levels in BM recipients compared with PBSC recipients. The mean of the maximum of all PCR values was 4-fold higher in BM recipients than in PBSC recipients (P = .20).

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• Figure 3. 

  The probability of molecular relapse, defined as a single qualitative PCR test, in CML-CP BM and PBSC recipients (P = .10).

Twelve (41%) of 29 BM recipients and 9 (31%) of 29 PBSC recipients had 1 positive PCR test on at least 1 occasion without clinical relapse. All nonrelapsed patients, except 1 BM recipient, were negative by PCR testing at last contact at a median of 1307 days (range, 293–2569 days) after transplantation. By quantitative RT-PCR testing, this BM recipient had an undetectable bcr-abl copy number. Only the qualitative PCR test, which is more sensitive, was positive. In several studies, the association between molecular relapse and clinical relapse is not significant for patients within 3 months of transplantation [13]. Nine CP patients (6 BM and 3 PBSC recipients) had persistent CML detectable only by PCR more than 100 days after transplantation. All 9 patients achieved a molecular remission. Four patients were treated with INF for 12 months, 2 had immunosuppressive medications withdrawn, and 1 had chronic GVHD during continued administration of immunosuppressive medications. Two patients had a spontaneous molecular remission without intervention or evidence of GVHD. These 2 patients had only intermittently positive PCR tests.

Graft-versus-host disease 

Thirty-nine patients had evidence of clinical extensive chronic GVHD. Four patients were excluded from this analysis because of death before day 100 (1 BM recipient and 3 PBSC recipients). The cumulative incidence of chronic GVHD at 3 years was 50% in BM recipients and 59% among PBSC recipients (P = .46). Among CP patients, the incidence of chronic GVHD at 3 years was 40% in BM recipients and 59% among PBSC patients (P = .11). Information regarding the number and timing of chronic GVHD therapies was available for 29 of 39 patients (15 BM and 14 PBSC recipients). Among the 29 patients, the median number of GVHD therapies administered (n = 2; range, 1–6) was the same for BM and PBSC recipients, but there was a trend toward more GVHD therapy in the PBSC group (P = .13). Data with regard to immunosuppression duration and cessation were available for 38 of 39 GVHD patients (20 BM and 18 PBSC recipients). Among surviving patients without evidence of relapse, the percentage of patients able to discontinue GVHD treatment within 3 years after transplantation was higher among BM recipients (49%) than among PBSC recipients (33%; P = .31); this suggested a trend toward a longer duration of immunosuppression in PBSC recipients.

Quality of life 

Karnofsky performance status (KPS) was measured at each institution for almost all patient visits. Mean scores are reported at yearly intervals for CP patients by cell source in Table 3. By year 2, mean KPS was >89% in both PBSC and BM recipients. We found no statistically significant difference in KPS among CP PBSC recipients as compared with BM recipients, except in the fourth year.

Table 3. Mean Karnofsky Performance Status for CP Patients by Cell Source for Years 1 to 5 after Transplantation

Twenty-five of 54 patients who underwent transplantation at the FHCRC submitted at least 1 questionnaire between 3 and 5 years after transplantation (12 BM and 13 PBSC recipients). Of the 44 CP patients treated at the FHCRC, 23 patients (52%) have submitted at least 1 questionnaire (10 BM and 13 PBSC recipients). The small number of respondents limits the statistical power of comparisons between these groups. Overall, there were no significant differences in symptom reporting, overall health rating, ability to work, depression, or emotional well-being between the groups stratified by cell source. Sixty-six percent of the respondents rated their health as excellent or very good. Seventy-three percent reported that their physical and emotional health only rarely or never interfered with their social activities. All reported feeling depressed only some of the time or never. Thirty-five percent reported that they accomplished less because of physical health problems, and 17% reported accomplishing less because of emotional health problems. Thirty percent reported some difficulty with memory. Sixty-two percent were working full-time and 13% part-time. The remaining respondents were attending school, working part-time, or working at home. Seventy-four percent of the respondents reported no problems with pain, 30% percent reported worry about health problems, 26% percent reported difficulty with sleep, and 39% percent reported problems with sexual function.

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Discussion 

Among CP-CML patients, we found no statistically significant difference in the incidence of acute or chronic GVHD, NRM, or OS between BM and PBSC recipients. However, there was a trend toward a higher cumulative incidence of relapse in BM recipients (7% versus 0%; P = .10) and a higher cumulative incidence of chronic GVHD in PBSC recipients (59% versus 40%; P = .11) at 3 years. The trend toward an increased relapse incidence in BM recipients persists with longer follow-up (13% versus 3%; Figure 2). There have been several multicenter randomized trials [3, 4, 5, 6], single-institution randomized trials [7, 8], and retrospective database studies [17, 18] comparing outcomes of BM versus PBSC transplants. Most studies show no difference in acute GVHD. Only 1 randomized trial found a statistically significant increase in acute GVHD with the use of PBSCs [6]. With respect to chronic GVHD, 2 multicenter trials [3, 6], the largest retrospective database cohort study [17], and 3 other retrospective and cohort studies [19, 20, 21] have found an increased incidence of chronic GVHD with PBSCs. Updates from 2 randomized trials have also reported that PBSC patients seem to have more protracted or refractory GVHD [12, 22]. It remains unclear whether the stem cell source affects OS and DFS. One study reported improved OS that was due to lower NRM in PBSC recipients, and 2 studies have suggested that with advanced myeloid malignancies, DFS was improved in PBSC recipients [4, 5].

Our study focused on a randomized cohort of CML patients to clarify the risks associated with PBSCs compared with BM as a stem cell source, particularly in CML-CP patients. Similar to previously published studies, the data indicate that CML patients receiving PBSCs, as opposed to BM, engraft more quickly and have no clear difference in the incidence of acute GVHD. In CML-CP patients, there was no statistically significant difference in the incidence of chronic GVHD or the number of chronic GVHD treatments by cell source. However, there was a trend toward an increased incidence of chronic GVHD in PBSC recipients (59%) compared with BM recipients (40%; P = .11). There was also a trend in PBSC recipients toward a longer duration of immunosuppression compared with BM recipients. There was no difference in OS or DFS by cell source. This finding is not surprising given the excellent outcomes for CP disease, the relatively small number of patients in this study, and the relatively short follow-up time. Most notably, however, there was a trend toward fewer relapses in CP patients receiving PBSCs.

We acknowledge several unanticipated limitations to this study. The accrual target was not achieved, and the analysis was performed prematurely with regard to patient numbers. Thus, differences between the BM and PBSC groups may exist that were not identified in this analysis. However, CP patients were well matched by the process of randomization for many assessed factors. We found no significant difference between BM and PBSC recipients for several known factors that could alter relapse rates, such as patient age, diagnosis white blood cell count, or time to transplantation.

Given the impressive progression-free survival of 88% reported for imatinib mesylate at the 30-month update of the IRIS trial [23] and the relatively minimal side effects of this drug, quality-of-life issues and outcomes in patients with recurrent malignancy after transplantation have become increasingly important. The 5-year OS after transplantation is >75% in both matched related and unrelated donor recipients, and relapse after stem cell transplantation occurs in only 10% to 20% of CP-CML patients [24]. All CP patients and 1 AP patient with recurrent disease were successfully treated. Only 3 AP patients died as a consequence of recurrent CML. Our data suggest that many CML patients participating in this trial have a good quality of life, and this finding does not differ significantly by stem cell source. KPS by year 2 after transplantation show that most patients are functioning at >90% KPS, irrespective of cell source. KPS, however, probably does not adequately address many of the nonquantifiable factors that comprise quality of life. Self-report data from the questionnaires, however, indicated that most respondents rated their health as excellent or good, were working full-time, and were not significantly limited by health or emotional problems.

The trend toward a higher relapse rate in BM recipients may suggest that PBSCs augment the GVL effect that is so important in hematopoietic stem cell transplantation for the treatment of CML [25, 26]. The findings of a higher probability of molecular relapse in BM recipients and the trend toward higher quantitative bcr-abl transcript levels in BM recipients may support this possibility.

From these and other data, there does not seem to be a major disadvantage in using PBSCs rather than BM as a source of stem cells for CML-CP disease. If, with longer follow-up and more detailed retrospective analysis, the finding of a lower rate of relapse is statistically significant in PBSC recipients, PBSCs may be the preferred cell source because of a possible increased GVL effect. However, this effect is counterbalanced by an increased incidence of chronic GVHD that has been found to be statistically significant in other studies.

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Acknowledgments 

Supported in part by National Institutes of Health grant nos. CA-18029 and CA-49605.

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